**Acknowledgements**

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

enzymes and increased levels of ROS/RNS [151].

quality cellular housekeeping [150].

(GPx) [151].

**7. Conclusions**

mechanisms.

GLP1/exendin-4 in food intake.

regulated by insulin/IGF signaling and both AMPK and mTORC1 pathways, which are in turn regulated by nutrient levels, whose signals converge on several targets: FOXO, nuclear factor: erythroid-derived 2-like 2 (NRF2), tumor protein p53, and sirtuins (SIRT) in order to control metabolic homeostasis, oxidative stress, and

PASK−/− mice may avoid several of the deleterious defects induced by the aging process [151]. Aged PASK−/− mice maintain both low blood glucose values and insulin concentrations similar to young WT mice. They do not develop glucose intolerance or insulin resistance, as confirmed by a normal HOMA-IR index. These effects correlate with a high expression of the longevity gene *FoxO3a* and the transcription factor NRF2, as the main regulator of the redox balance [151]. Signaling through the system NRF2/KEAP1: kelch-like ECH-associated protein 1 regulates the transcription of enzymes that protect cells against oxidative stress [152]. An elevated expression of glutamate-cysteine ligase modifier subunit (GCLm) and heme oxygenase-1 (HO1) have been found in aged PASK−/− mice under fasted conditions. The efficiency of this redox system decreases in step with aging in WT mice, significantly diminishing the antioxidant response [153]. Likewise, PASK deficiency prevents the drastically age-related decrease in the expression of several antioxidant enzymes under basal conditions, such as catalase (CAT) and glutathione peroxidase

In relation to the maintenance of the mitochondrial function and energy homeostasis, we have confirmed that the expression of the several transcription factors and nuclear receptors needed to maintain mitochondrial biogenesis (*Ppargc1a, Sirt1* and *Nrf2)* are affected in fasted aged WT mice [151] in accordance with the previous literature that relates aging to a decrease in cellular energy input [154], an increase in oxidative stress [155], and the mitochondrial dysfunction of cellular redox homeostasis [156, 157]. However, the expression of *Nrf2, Ppargc1a, Ppar*γ and *Sirt1* increases under fasting in aged PASK−/− mice. This means they maintain lower levels of ROS/RNS, while aged WT mice record a lower expression of antioxidant

We might therefore contend that some of the dysfunctions produced during aging in PASK−/− mice could be related to hormetic responses. Slight toxic effects can generate beneficial actions that compensate for the initial damage and even improve cellular health [158]. Aging decreases *Pask* expression in the liver of WT mice perhaps as a compensatory mechanism. PASK−/− mice maintain the same blood

PASK function could be critical for preserving the nutrient effect on hypothalamic AMPK and mTORC1/S6K1 pathways and maintain the regulatory role of

PASK regulates the hepatic glucose sensor GCK and AKT, an insulin signaling intermediators, and glucose and lipidic metabolism through the regulation of the key genes and proteins required during hepatic fasting/feeding adaptation. Moreover, PASK deficiency improves mitochondrial biogenesis and antioxidant

HFDs alter the adaptive response of *Pask* gene expression to fasting/feeding. PASK deficiency eliminates many of the harmful effects HFDs have on the liver, thereby decreasing the lipid depots. PASK deficiency decreases the expression of several transcription factors stimulated under fasted conditions to promote the expression of the gluconeogenic enzymes and those promoting the expression of

glucose values as young WT mice, and do not develop insulin resistance.

**358**

This work was supported by grants from the Complutense University-Banco Santander Funding Programme for the Creation and Consolidation of Research Teams.

We thank Pilar Dongil for their contribution to this work.
